tbuckley/cabot-search huggingface dataset:
Abstract 1679: Unraveling the function of TRAF2 and NCK interacting kinase (TNIK) in high-grade serous ovarian cancer
Authors: Noah Puleo, Michele Cusato, Dylan Carvette, Chantelle Husdon, Analisa DiFeo
Journal: Cancer Research (2023)

Abstract The large majority of high grade serous ovarian cancer (HGSOC) patients will eventually become resistant to platinum-based chemotherapy, highlighting the urgent need to develop novel therapeutics targeting recurrent, platinum-resistant disease. To study this, our lab generated two patient derived platinum-resistant tumor spheres from platinum-sensitive primary patient cells to better understand the biology behind recurrent disease and identify novel therapeutic targets. Utilizing an artificial intelligence (AI) powered model, we screened a library that consisted of compounds predicted to target known or postulated resistance mechanisms and involved a novel therapeutic target. From this screen, we identified a TNIK kinase inhibitor as the only compound to effectively kill HGSOC spheres while sparing non-malignant fallopian tube cells. TNIK plays a key role in Wnt pathway activation, which our lab has previously shown to be critical in driving cancer stemness and epithelial ovarian cancer platinum resistance. Additionally, patient data shows that TNIK is amplified in ovarian cancer more than any other cancer type and is highly activated in ovarian cancer patients. We found that this compound was able to decrease overall Wnt activity in our platinum-resistant cells and could resensitize our platinum-resistant cells to cisplatin. This work demonstrates the abilities of using AI to expedite the drug discovery process as well as uncover novel therapeutic targets which may lead to future therapeutic strategies for HGSOC patients who no longer respond to standard of care platinum chemotherapy. Citation Format: Noah Puleo, Michele Cusato, Dylan Carvette, Chantelle Husdon, Analisa DiFeo. Unraveling the function of TRAF2 and NCK interacting kinase (TNIK) in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1679.
Abstract 2545: NNMT is a novel effector of EGFR driven glioblastoma malignancy
Authors: Lianping Ma, Ming Li
Journal: Cancer Research (2023)

Abstract Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that catalyzes the conversion of methyl groups from S-adenosyl-L-methionine (SAM) to nicotinamide (NAM) to generate S-adenosine hyperblastoids (SAH) and 1-methylnicotinamide (MNA). Upregulation of NNMT has been observed in a variety of cancers, including glioblastoma. The mechanism by which NNMT is overexpressed in glioblastoma remains largely unknown. Epidermal growth factor receptor (EGFR) gene amplification or mutation is one of the most common genetic lesions in glioblastoma, and EGFRvIII is the most common mutant contributing to glioblastoma cell proliferation, invasion, therapeutic resistance, metastasis, and stemness. In this study, we show that activation of wild-type EGFR by EGF or the constitutively active mutant EGFRvIII promoted NNMT expression in established glioblastoma cell lines and glioblastoma stem-like cells via the p38 mitogen-activated protein kinase pathway. Furthermore, we identified STAT1 as a downstream transcription factor required for EGFR/EGFRvIII-induced NNMT upregulation. Knockdown of NNMT by RNA interference in glioblastoma cells significantly inhibited EGFRvIII-promoted glioblastoma cell invasion and proliferation in vitro. Targeting NNMT inhibited EGFRvIII-driven glioblastoma tumorigenicity and prolonged survival of tumor-bearing mice. Clinically, NNMT was highly expressed and positively correlated with EGFR expression in human glioblastoma tumors. Taken together, these findings establish NNMT as a previously unknown downstream target gene of EGFR/EGFRvIII expression and nominate it as a new potential therapeutic target for inhibiting EGFRvIII-driven glioblastoma. Citation Format: Lianping Ma, Ming Li. NNMT is a novel effector of EGFR driven glioblastoma malignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2545.
Abstract 1212: Horizontal transfer of functional human papillomavirus genes in head and neck squamous cell carcinoma
Authors: Jason Tasoulas, Wendell Gray Yarbrough, Natalia Issaeva
Journal: Cancer Research (2023)

Abstract Human papillomavirus (HPV) infections are currently associated with more than 70% of oropharyngeal squamous cell carcinomas (OPSCCs). HPV-positive OPSCCs display a distinct biologic behavior and treatment response and thus are now considered a distinct entity than HPV-negative OPSCCs. However, the underlying process of HPV-related OPSCC carcinogenesis is not entirely clear. HPV as a driver of cervical carcinogenesis is well-characterized with identification of a canonical mechanism dependent on HPV DNA integration, loss of HPV E2 gene expression, and increased expression of HPV E6 and E7 oncogenes with no active infection present in malignant lesions. However, whole genome sequencing found no HPV DNA integration in ~25% of HPV-associated OPSCC, suggesting an alternative mechanism of HPV carcinogenesis. Expression of all HPV genes, including self-assembling capsid proteins, in a substantial portion of HPV+ OPSCC, led us to hypothesize that tumors with episomal HPV are capable of transferring HPV genes to surrounding cells and that HPV gene transfer contributes to carcinogenesis in this subset of OPSCC. Our data support this hypothesis, showing that growth media from HPV+ OPSCC cell lines, as well as isolates from HPV+ tumors or nodal metastases, effectively transferred functional HPV genes to cells lacking HPV. The HPV DNA Transferring Agent (HDTA) derived from HPV+ OPSCC contained HPV L1 capsid protein and intact HPV genome protected from DNAase degradation. Initial characterization revealed that anti-L1 antibody blocked gene transfer and that exposure of cells to the HDTA initiated a robust innate immune response in recipient cells. Negative staining of HDTA isolate from metastatic lymph nodes revealed many pleomorphic, electron-dense particles with diameter ranging between 20 and 80nM, with approximately 40% of particles being between 50 and 60nM, consistent with the size of HPV. We propose that development and/or maintenance of OPSCCs depend on continuous production of HDTA capable of transferring HPV genes into neighboring cells. This paradigm of tumorigenesis/maintenance in OPSCC is most likely to apply to cancers lacking HPV integration, but may also apply to tumors with integration, since recent data suggested that integrated HPV may excise from the genome to recreate a transient episomal like structure, even containing cellular DNA. Our findings offer novel insights into oropharyngeal carcinogenesis and suggest targeting HDTA as a new therapeutic strategy for HPV-positive OPSCCs. Citation Format: Jason Tasoulas, Wendell Gray Yarbrough, Natalia Issaeva. Horizontal transfer of functional human papillomavirus genes in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1212.
Abstract 1278: ID3 controlled dynamic Pyk2 localization is important for the mobility of cancer stem cells
Authors: Jayanta Das, Alok Deoraj, Deodutta Roy, Quentin Felty
Journal: Cancer Research (2023)

Abstract Treatment of brain metastases remains a clinical barrier in breast cancer patients. Secondary breast tumors in the brain are reported to be enriched with breast cancer stem cell (BCSC) markers suggesting that BCSCs infiltrate the brain. Brain infiltration by BCSCs is complex involving detachment from the primary tumor, entering the blood, surviving the microvascular niche, and crossing the blood brain barrier (BBB). It is critical to understand how BCSCs move through the BBB to prevent brain metastases. Nuclear respiratory factor 1 (NRF1) transcription factor, Pyk2 non-receptor tyrosine kinase, and inhibitor of differentiation protein 3 (ID3) have been shown to contribute to the pathogenesis of cancer through inducing CSCs or increasing mobility of these cells. Recently, we showed that NRF1-induced BCSCs crossed the BBB which were guided by ID3 overexpressing endothelial stem cells. In this study, we investigated the NRF1/ID3/Pyk2 axis contributing to BCSCs mobility. NRF1 promoted migration of BCSCs and mesenchymal MDAMB231 cells through brain endothelial cells cultured with astrocytes. ID3 overexpressing endothelial cells promoted adhesion with BCSCs and mobility of BCSCs across the BBB model. In addition, ID3 controlled Pyk2 localization which is important for mobility of stem cells and cancer cells. Endothelial cells were treated with a known risk factors for breast cancer, 17β-estradiol (E2) and environmental pollutant PCB153. Treatment with PCB153 or E2 showed increased growth of BCSCs tumor spheroids and mobility of ESCs. Exosomal ID3 released from endothelial cells also supported the growth of BCSCs and provide the basis for paracrine effects by endothelial stem cells associated with breast tumors. These findings show for the first time a novel role for ID3 and Pyk2 by which endothelial stem cells support breast tumor metastases where they most likely facilitate the colonization, survival, and proliferation of BCSCs. This knowledge is important for pre-clinical testing of NRF1/ID3/Pyk2 modifying agents to prevent the spread of breast cancer to the brain. Citation Format: Jayanta Das, Alok Deoraj, Deodutta Roy, Quentin Felty. ID3 controlled dynamic Pyk2 localization is important for the mobility of cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1278.
Abstract 6195: Assessing replication stress as an actionable therapeutic opportunity in chordoma
Authors: Nindo Punturi, Lee Dolat, Wendy Leung, Joan Levy, Lee Zou, Daniel M. Freed, Gregory M. Cote
Journal: Cancer Research (2023)

Abstract Chordoma is a rare bone cancer with a high rate of disease recurrence and no approved systemic therapies. Tumor profiling studies indicate a significant number of chordomas are characterized by alterations in SWI/SNF chromatin remodeling and DNA damage repair genes, which have been associated with replication stress in other cancer types. We demonstrate here that preclinical chordoma models exhibit a replication stress phenotype and dependence on ATR activity. To assess the effect of ATR inhibition on cell viability, a panel of chordoma cell lines were treated with the ATR inhibitor elimusertib (BAY 1895344). In a subset of cell lines, elimusertib inhibited viability with low-nanomolar IC50 values. Upon treatment with the ATR inhibitor ceralasertib (AZD6738), DNA fiber assays revealed a mild decrease in replication fork speed and a significant increase in fork asymmetry in cells sensitive to ATR inhibitor, suggesting possible fork stalling or collapse in response to ATR inhibition. To assess genomic instability as a consequence of ATR inactivation and fork stalling or collapse, alkaline and neutral comet assays were performed to determine the presence of genome-wide ssDNA and/or dsDNA breaks, respectively. In a panel of chordoma PDX models, striking differential sensitivity to ATR inhibition was observed. In sensitive models, elimusertib (50 mg/kg, po, bidx3) promoted 85-90% tumor growth inhibition, in contrast to resistant models, where elimusertib treatment had no effect on tumor growth. Moreover, PDX models sensitive to ATR inhibition were sensitive to other therapies that exacerbate replication stress; for example, gemcitabine promoted multiple complete responses in a pediatric chordoma PDX model. Coupled with preclinical efficacy data, genomic and transcriptomic sequencing of differentially-sensitive chordoma models provided insight into the molecular factors associated with the replication stress phenotype in chordoma - illuminating potential biomarkers for patient selection. Finally, we explore various combination therapies and show that combining elimusertib with cisplatin or gemcitabine synergistically inhibits the viability of chordoma cell lines. Collectively, our data indicate that a subset of chordomas are characterized by intrinsic replication stress that can be therapeutically exploited by inhibiting ATR. Citation Format: Nindo Punturi, Lee Dolat, Wendy Leung, Joan Levy, Lee Zou, Daniel M. Freed, Gregory M. Cote. Assessing replication stress as an actionable therapeutic opportunity in chordoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6195.
Abstract 6151: Loss of GPR54 inhibits tumor growth by suppressing AKT/DDC signaling pathway in KRAS-mutant non-small cell lung cancer
Authors: Seo Yeon Lee, Yu-Jeong Choi, Hyun-Ha Hwang, Sooyeon Kang, Kangwook Lee, Seong-Gyu Ko
Journal: Cancer Research (2023)

Abstract Therapeutic targeting of KRAS-mutant lung cancers has remained a challenge. There are increasing evidence that KISS1/GPR54 signaling pathway is associated with the development of various cancer. Although KISS1 and GPR54 are expressed in the lung, their biological role in the lung tumorigenesis remains unclear. In this study, using the genetically engineered mouse models, we have identified that loss of Gpr54 inhibited Kras-driven lung tumorigenesis by suppressing pathways in oncogenesis such as the MAPK and AKT pathways and inducing apoptosis. Similarly, genomic inhibition of GPR54 suppressed cell proliferation, decreased ERK and AKT signaling pathway, and increased apoptotic cell death in NSCLC cells. RNA-sequencing analysis revealed that DDC expression and glycolysis gene sets were significantly changed in Gpr54 deficient mice. Interestingly, HIF-1α expression is regulated by GPR54/AKT/DDC signaling pathway in NSCLC cells, leading to glycolytic change. Genomic inhibition of DDC suppressed cell proliferation and enhanced apoptotic cell death in NSCLC cell lines. Also, pharmacological inhibition of GPR54 and DDC lower glucose consumption and lactate production in NSCLC cell lines. Taken together, we demonstrate GPR54, as a potential therapeutic target, suggesting a new strategy to cure for lung cancer patients. Citation Format: Seo Yeon Lee, Yu-Jeong Choi, Hyun-Ha Hwang, Sooyeon Kang, Kangwook Lee, Seong-Gyu Ko. Loss of GPR54 inhibits tumor growth by suppressing AKT/DDC signaling pathway in KRAS-mutant non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6151.
Abstract 922: Body composition and metabolic dysfunction really matter for the achievement of better outcomes in high-grade serous ovarian cancer
Authors: Mauricio A. Cuello-Fredes, Fernan Gomez, Ignacio Wichmann, Felipe Suarez, Sumie Kato, Jorge Brañes, Elisa Orlandini, Carolina Ibañez
Journal: Cancer Research (2023)

Abstract Our objective was to evaluate the impact of body composition (BC), beyond body mass index (BMI), and lipid metabolism disorders on therapeutic responses and outcomes in high-grade serous ovarian cancer (HGSOC).Methods: 123 and 415 patients with advanced HGSOC from two cohorts (PUC and TCGA) were analyzed. Databases containing clinical/genomic variables were built-up. BC was estimated using the measurement of adiposity (e.g., Whole body Adipose Tissue [WBAT]) and muscle mass (Lumbar muscle area to vertebral body at L4-level, [PLVI]) by CT-scan. A list of 425 genes linked to obesity and lipid metabolism was used to identify clusters using non-negative matrix factorization. GSEA, Gene Ontology, KEGG pathways enrichment, and Ecotyper analyzes were also made. Survival curves and Cox-regression models were also built-up. Results: We identified four BC types and two clusters that, unlike BMI, effectively correlate with survival regardless of achieving optimal debulking or complete response. Mention deserves central sarcopenia, which was associated with worse survival in any condition. So also, that recovering a normal BC and adding medications to correct metabolism disorders (e.g., statins) could have a positive impact on outcomes. Along with this, we showed that micro-environments depleted of immune cells predominate in HGSOC, something more evident in the BC type (High WBAT/Low PLVI) and cluster (Obesity/Lipid Metabolism Type I) with worse prognosis. Conclusions: Here, we demonstrate the relevance of BC and lipid metabolism disorders in determining therapeutic responses and long-term outcomes. Also, the importance of incorporating corrective measures addressing these disorders to obtain better results. (Research supported by Fondecyt 1201083) Citation Format: Mauricio A. Cuello-Fredes, Fernan Gomez, Ignacio Wichmann, Felipe Suarez, Sumie Kato, Jorge Brañes, Elisa Orlandini, Carolina Ibañez. Body composition and metabolic dysfunction really matter for the achievement of better outcomes in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 922.
Abstract 2827: Application of AZD2281 combine with radiation therapy in glioblastoma
Authors: Tsal-Lan Liao, I-Tsang Chiang, Yuan Chang, Fei-Ting Hsu
Journal: Cancer Research (2023)

Abstract Glioblastoma (GBM), can be divided into primary tumors from brain tissue (&amp;gt;90% of all cases) and secondary tumors that progress from low-grade gliomas. The current GBM treatment strategy is chemotherapy drug temozolomide (TMZ) combined with radiotherapy (RT), which has limited treatment effect, poor prognosis, high recurrence rate, and short prognosis survival time. Recently, studies indicated that breast cancer susceptibility gene 1/2 (BRCA1/2) mutations are frequently occur in GBM, while few studies have explored this pathway in depth. At present, AZD2281 (PARP Inhibitor) has been used to treat breast cancer and ovarian cancer patients with BRCA1/2 mutation...etc. Whether AZD2281 can play a role in affecting the relevant pathways after BRCA1/2 mutate GBM patients, and the possible mechanism and benefit of combined RT are the focus of this study. AZD2281 is the first Poly (ADP-ribose) polymerase (PARP) inhibitor approved by the U.S. Food and Drug Administration (FDA) for the treatment of germline BRCA mutation-associated ovarian cancer. AZD2281 is a targeted therapy that used to block DNA Damage Response (DDR) in cells/tumors deficient in homologous recombination repair (HRR). After RT, there may be a phenomenon of DNA repair; therefore, AZD2281 can be used to disrupt the repair process. At the beginning, we used RSI analysis to confirm that patient with higher expression level of BRCA1 may relatively resistance to RT. To overcome this issue, we identified the effect of AZD2281 combined with RT on GBM cells (BRCA1/2 higher and lower expression cells) by (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT assay), and colony formation. The internal/external apoptosis pathways (Caspase-3/Caspase-8/Caspase-9) and TUNEL assay were used to prove the superior apoptosis effect of AZD2281 combined with RT as compared to single treatment. Additionally, cells lower BRCA1 expression level (U87 and U251 siBRCA1) may sensitive to RT treatment. In our DNA damage, DNA fragmentation, and transwell invasion/migration results, we showed that the combination of AZD2281 and RT may effective induce DNA damage. In our animal data, we proved that combination therapy can effective suppression tumor growth and apoptosis-related protein signaling increased in DNA damage by IHC (p-ATM/p-CHK2/Caspase-3/Caspase-8/Caspase-9). In conclude, we suggested that AZD2281 can be used as a radiosensitizer to sensitize GBM patient to RT, which is dependent to BRCA1 expression. Citation Format: Tsal-Lan Liao, I-Tsang Chiang, Yuan Chang, Fei-Ting Hsu. Application of AZD2281 combine with radiation therapy in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2827.
Abstract 6149: STAT3 activation promotes invasiveness and cancer stemness in lung cancer
Authors: Sai Fung Yeung, Sze Man Chan, Chun Ho Law, Hoi Yin Chan, Kwok Wing Tsui
Journal: Cancer Research (2023)

Abstract Lung cancer is the leading cause of cancer-related death worldwide, featuring a high incidence and low 5-year survival rate. Nearly 40% of patients are diagnosed with metastatic disease when they are first presented to the clinic. However, drug intervention targeting established metastatic tumors remains challenging, a better understanding of therapeutically exploitable mechanisms is urgently needed. This present study aims to explore novel therapeutic intervention against metastatic lung cancer. To understand the tumor-cell-intrinsic pathway that drives metastatic progression, we generated a highly invasive subline of lung cancer cell - A549 (ATCC, USA) by serial selections for Matrigel-coated transwells. The invasive subline A549-i3 shows about 5 times higher invasion potential than the parental cell line A549-Par (p&amp;lt;0.05, Student t-test). Colony-formation Assay and suspension growth in ultra-low attachment plates were used to measure the 2D proliferation ability and anoikis resistance, albeit with no difference. The differential efficacies between A549-Par and A549-i3 against multiple pathway inhibitors were screened using MTT assay in vitro. Notably, A549-i3 is more sensitive towards napabucasin (STAT3 inhibitor) and tipifarnib (FTase inhibitor) when compared with A549-Par, suggesting their potency in targeting cancer stemness and addicted oncogenic driver. Furthermore, napabucasin reduced the migration and invasion abilities of A549-i3 to similar extent as their parent counterpart. Overall, our preliminary data identified STAT3 as a potential therapeutic vulnerability in highly invasive cancer cells. Future work will be focused on identifying pathways responsible to sensitize highly invasive NSCLC cells toward STAT3 inhibition using multiomics approach. This project was supported by the Research Impact Fund (Ref. No.: R4015-19) from the Research Grants Council in Hong Kong. Citation Format: Sai Fung Yeung, Sze Man Chan, Chun Ho Law, Hoi Yin Chan, Kwok Wing Tsui. STAT3 activation promotes invasiveness and cancer stemness in lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6149.